?A major need exists for new treatments for anemias associated with chronic disease states, collectively known as anemia of chronic disease/inflammation (ACDI). These anemias significantly contribute to national morbidity, mortality, and health care expenses. The current treatments are expensive, inconsistently effective, and associated with adverse side effects. The pathogenetic mechanisms of ACDI involve complex perturbations of erythroid homeostasis resulting from inflammatory signaling. A key element in most cases consists of insufficient delivery of iron to bone marrow progenitors: erythroid iron restriction. Accordingly, most current and next-generation therapeutic strategies involve enforcing iron delivery by circumvention of endogenous iron regulatory mechanisms; these approaches thus pose risks of chronic iron overload. Our lab has pioneered an alternative approach to ACDI involving reversal of the erythroid response to iron restriction. This approach exploits the intrinsic ability of erythroid progenitors to regulate global iron metabolism in accordance with erythropoietic demand. Specifically, direct stimulation of erythropoiesis enhances iron absorption and distribution in a physiologic, as-needed manner that avoids iron overload. Accordingly, we have identified aconitase enzyme inactivation as a mediator of the erythroid iron restriction response and have demonstrated reversal of this response by providing the downstream metabolite isocitrate. The therapeutic potential of isocitrate has been demonstrated in several rodent model systems including: murine iron deficiency, rat chronic arthritis, murine chronic arthritis, and murine acute inflammation. Therapeutic targeting of the aconitase-isocitrate pathway in ACDI offers an alternative approach to IV iron or hepcidin inhibition, providing advantages of lower cost, no risk of iron overload, and oral bioavailability. This approach has been validated in multiple animal models, and key elements of the mechanism have now been identified. The proposed studies will compare isocitrate and a series of analogs in a murine arthritis model of ACDI for treatment optimization and characterization of pharmacologic properties.